B lymphocytes are the central mediators of humoral immunity. Aberrant B cell function contributes to many autoimmune diseases and age-related defects in humoral immunity, with malignant B cells representing the primary cell type in leukemia and lymphoma. B cell function is regulated by cell-surface molecules that generate transmembrane signals, regulate intercellular communication, and direct lymphocyte development. The aim of these studies is to examine the in vivo function of CD20, a B cell-specific cell-surface protein, and other members of the MS4A gene family that we have recently identified. CD20 is a membrane embedded component of an oligomeric complex that regulates transmembrane Ca2+ transport and cell cycle progression. Anti-CD20 immunotherapy has become a standard treatment for non-Hodgkin's lymphoma, and shows great promise for the treatment of autoimmunity. Despite this, relatively little is known about the function of CD20 in vivo and why it is such an effective target for immunotherapy. Since mechanistic and outcome studies are difficult and expensive in humans and other primates, we have developed mouse models for anti-CD20 mAb therapy that allows us to determine the molecular basis for therapeutic efficacy in vivo. We hypothesize that the molecular structure and function of CD20 and other MS4A family members makes them unique targets for effective therapy. To test this hypothesis, we will determine how CD20-directed therapies regulate B cell function in vivo and determine whether other members of the MS4A gene family are also effective immunotherapy targets. In Specific Aim 1, the functional significance and consequences of anti-CD20 mAb therapy will be assessed in normal mice. In Specific Aim 2, the molecular and cellular basis for B cell clearance will be determined. In Specific Aim 3, the efficacy and mechanism of mAb therapy will be assessed in mouse models of lymphoma. Specific Aim 4 will focus on the structure and expression of 20 newly-identified members of the MS4A gene family in mouse and man to determine whether they are appropriate targets for immunotherapy. Since CD20 provides an important regulatory checkpoint for ablating or adjusting B cell development and function, a molecular understanding of how it and other MS4A family members function will provide new avenues for modulating humoral immunity and effectively treating human disease.